Memantine Hydrochloride of Merz-Germany became available in 1982 and is still used for treatment of Parkinson's disease, Neuropathic Myotonia and Dementia Syndrome. The drug is sold under the trade name Akatinol in a few countries such as Germany. Memantine Hydrochloride was previously found to act as NMDA (N-methyl-D-aspartate) receptor antagonist. Now, Memantine Hydrochloride has been approved as an effective drug for the treatment of moderate to severe AD by the European Union and it has become the first approved drug for the treatment of moderate to severe AD. In USA, the phase III clinical study has been completed and a NDA has been submitted to FDA. Because there is no effective medicine for the treatment of moderate to severe AD, Memantine Hydrochloride is of great interest. The drug has profound potential as a medicine for treating moderate to severe Vascular Dementia. This condition is also without an effective treatment.
With regard to the synthesis of Memantine Hydrochloride, there are two method reported in the literature, one is U.S. Pat. No. 3,391,142 using acetonitrile/sulfuric acid and the other is U.S. Pat. No. 4,122,193 using urea in the synthesis.
In the method of U.S. Pat. No. 3,391,142, 1,3-dimethyl adamantane is bromized to yield 1-bromo-3,5-dimethyl adamantane, which is then subjected to acetylation and ammonization in the presence of acetonitrile and sulfuric acid, extracted with benzene, dried and concentrated to yield 1-acetamino-3,5-dimethyl adamantane. After the alcoholysis with sodium hydroxide and diethylene glycol, extraction in benzene and concentration, memantine crude was obtained, which was then salified with hydrochloric acid, re-crystallize with ethanol/ether and purified to yield Memantine Hydrochloride.
This method uses acetonitrile, benzene and ether, which are hazardous to environment and human, in the process of acetylation, ammonization and re-crystallization. Furthermore, this method is difficult to hydrolyze acetyl compound, produces many by-products and darkens the product due to the reaction of long duration. It is difficult with this method to meet the purity standards for pharmaceutical use. Therefore, it is necessary to improve this method.
The method of U.S. Pat. No. 4,122,193 uses 1-bromo-3,5-dimethyl adamantane as the raw material, which reacts with urea at 220° C. in tube sealing to yield agglomerate product. The product is milled and mixed with water into mash, then acidified to adjust pH between 3 and 5. Impurities are removed by ether extraction. The aqueous layer is basified to a pH of between 12 and 13. After extracted with ether several times, the organic layers is combined, dried, salified by inletting HCl gas to yield Memantine Hydrochloride. This method adopts tube sealing, and the high reaction temperature may cause the agglomeration of product. As a result, it is difficult industrialize this method.